Shekman L. Wong

Evaluation of Rifampin's Transporter Inhibitory and CYP3A Inductive Effects on the Pharmacokinetics of Venetoclax, a BCL-2 Inhibitor: Results of a Single- and Multiple-Dose Study.

Venetoclax is a selective, potent, first‐in‐class B‐cell lymphoma‐2 inhibitor that has demonstrated clinical efficacy in a variety of hematological malignancies. A single‐dose and multiple‐dose rifampin study was conducted to evaluate the effect of CYP3A induction and transporter inhibition on the pharmacokinetics of venetoclax. Subjects received a single dose of venetoclax 200 mg on day 1 of period 1 and days 1 and 14 of period 2, a single dose of rifampin 600 mg on day 1 of period 2, and rifampin 600 mg once daily on days 5 through 17 of period 2. Blood samples were collected up to 96 hours after each venetoclax dose on day 1 of period 1 and days 1 and 14 of period 2. Compared with venetoclax alone, coadministration with a single dose of rifampin increased venetoclax Cmax and AUC∞ by 106% (90%CI, 73%–145%) and 78% (90%CI, 50%–111%), respectively, whereas coadministration with multiple doses of rifampin decreased venetoclax Cmax and AUC∞ by 42% (90%CI, 31%–52%) and 71% (90%CI, 66%–76%), respectively. It was possible to isolate the net effect of chronic CYP3A induction from acute P‐glycoprotein (P‐gp) inhibition by comparing venetoclax exposures following coadministration with multiple doses of rifampin versus a single dose of rifampin, which showed that CYP3A induction decreased venetoclax Cmax and AUC by 72% and 84%, respectively. These results are consistent with venetoclax being a P‐gp substrate and indicate that CYP3A plays a major role in venetoclax metabolism. Prescribers should consider agents with little or no CYP3A induction during treatment with venetoclax.

Effect of Low‐ and High‐Fat Meals on the Pharmacokinetics of Venetoclax, a Selective First‐in‐Class BCL‐2 Inhibitor

Venetoclax is a selective, first‐in‐class, B‐cell lymphoma‐2 inhibitor that has demonstrated clinical efficacy in several hematological malignancies. Two studies evaluated the relative bioavailability of venetoclax in healthy subjects: (1) a bioequivalence study to compare the bioavailability of the film‐coated tablet with that of an earlier uncoated tablet and (2) a food effect study to evaluate the effect of food on venetoclax pharmacokinetics. Both studies were open‐label, single‐dose, crossover studies. In the bioequivalence study, 15 subjects received a single dose of venetoclax 50 mg under nonfasting conditions, in each of 2 periods; one period used the uncoated tablet, and the other used the film‐coated tablet. In the food effect study, 24 subjects received a single dose of venetoclax film‐coated 100‐mg tablet under fasting conditions, after a low‐fat breakfast or after a high‐fat breakfast in different periods. The venetoclax film‐coated tablet was bioequivalent to the uncoated tablet, which indicates that the film coating does not affect bioavailability. The median Tmax of venetoclax was delayed by about 2 hours when administered with food. Compared with fasting conditions, Cmax and AUC increased by approximately 3.4‐fold following a low‐fat breakfast. High‐fat meals increased Cmax and AUC by approximately 50% relative to low‐fat meals. The mean terminal half‐life was comparable between the high‐fat meal and fasting conditions (19.1 versus 16.1 hours). Based on these results and the venetoclax exposure–response profile, venetoclax should be administered with food and without specific recommendations for fat content to ensure adequate and consistent bioavailability.

Effects of divalproex sodium on amitriptyline and nortriptyline pharmacokinetics.

Divalproex sodium has been found to be efficacious in the prophylaxis of migraine headaches and the management of the manic phase of bipolar syndrome. Because amitriptyline is also prescribed in these patient populations, data are needed on their potential for interaction.

Pharmacokinetics of Subcutaneous Recombinant Methionyl Human Leptin Administration in Healthy Subjects in the Fed and Fasting States Regulation by Gender and Adiposity

AbstractBackground: Recombinant methionyl human leptin (r-metHuLeptin) has demonstrated efficacy in improving hormonal and metabolic parameters in leptin-deficient states, and it has been suggested that leptin replacement may reverse metabolic adaptations during weight loss interventions. The pharmacokinetics of subcutaneously administered r-metHuLeptin have been recently published, but whether pharmacokinetic parameters are altered by short-term fasting, adiposity and/or gender has not yet been evaluated. Objective: The objective of this study was to characterize pharmacokinetic parameters following subcutaneous r-metHuLeptin administration at doses in the physiological to supra-physiological to pharmacological range in the fed state and during 3-day complete fasting in lean and obese subjects, including both men and women. Methods: We analysed pharmacokinetic profiles in five lean men, five obese men and five lean women following subcutaneous administration of physiological (0.01 mg/kg), supra-physiological (0.1 mg/kg) and pharmacological (0.3 mg/kg) doses of r-metHuLeptin given once in the fed state and once daily during 3-day complete caloric deprivation (fasting). Results: With r-metHuLeptin administration at 0.01 mg/kg, leptin concentrations ranged up to ∼7 ng/mL in lean men, ∼20 ng/mL in obese men and ∼30 ng/mL in lean women in the fed state. There was a significant effect of 3-day fasting: it decreased baseline leptin concentrations, peak serum concentration (Cmax) and area under the serum concentration-time curve from time zero to infinity (AUC∞) [all p < 0.0001] and increased clearance (p < 0.001), most prominently in lean men (p < 0.0001 across the groups). Administration of r-metHuLeptin at 0.1 mg/kg resulted in leptin concentrations up to ∼70 ng/mL in lean men, ∼100 ng/mL in obese men and ∼150 ng/ mL in lean women in the fed state. At this dose, there was a similar effect of fasting on the pharmacokinetic parameters as well as a decrease in the terminal-phase elimination half-life (p = 0.02), consistent with increased clearance, but the effect of fasting was less pronounced overall than with the 0.01 mg/kg dose. With r-metHuLeptin administration at 0.3 mg/kg, leptin concentrations ranged up to ∼150 ng/mL in lean men, ∼300 ng/ mL in obese men and ∼400 ng/mL in lean women in the fed state. At this dose, fasting increased clearance to a lesser degree (p = 0.046), mainly in lean men, suggesting that the fasting-induced increase in leptin clearance by the kidneys can plateau. Within each group, the subjects lost ∼3–4 kg of bodyweight after 3 days of fasting (all p < 0.0001), but the amount and time course of weight loss did not differ according to the dose of r-metHuLeptin administered or the circulating leptin concentrations achieved. Conclusions: Short-term fasting in healthy individuals results in increased clearance of leptin; this contributes to hypoleptinaemia, which may serve as a signal to increase energy intake in the setting of caloric restriction. Obese individuals with greater energy stores at baseline have a blunted response to the fasting-induced increase in leptin clearance. Also, women have a differential response to fasting, with primarily decreased leptin production rather than increased clearance. These findings and the resulting formulas for calculating doses for r-metHuLeptin administration have important implications for future therapeutic use of r-metHuLeptin in conjunction with hypocaloric diets for the treatment of obesity.

Pharmacokinetics of Venetoclax, a Novel BCL‐2 Inhibitor, in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Non‐Hodgkin Lymphoma

Venetoclax is a selective BCL‐2 inhibitor that is approved in the United States for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least 1 prior therapy. The aim of this analysis was to characterize venetoclax pharmacokinetics in the plasma and urine of patients with hematological malignancies and evaluate the effect of dose proportionality, accumulation, weak and moderate CYP3A inhibitors, as well as low‐ and high‐fat meals on venetoclax pharmacokinetics. Patients received a once‐daily venetoclax dose of 20 to 1200 mg. Pharmacokinetic parameters were estimated using noncompartmental methods. Venetoclax peak exposures were achieved at 5 to 8 hours under low‐fat conditions, and the mean terminal‐phase elimination half‐life ranged between 14.1 and 18.2 hours at different doses. Venetoclax steady‐state exposures showed minimal accumulation and increased proportionally over the dose range of 300 to 900 mg. Low‐fat and high‐fat meals increased venetoclax exposures by approximately 4‐fold relative to the fasting state. Moderate CYP3A inhibitors increased venetoclax exposures by 40% to 60%, whereas weak CYP3A inhibitors had no effect. A negligible amount of venetoclax was excreted in the urine. In summary, venetoclax exhibits a pharmacokinetic profile that is compatible with once‐daily dosing with food regardless of fat content. Concomitant use of venetoclax with moderate CYP3A inhibitors should be avoided or venetoclax dose should be reduced during the venetoclax initiation and ramp‐up phase in CLL patients. Renal excretion plays a minimal role in the elimination of venetoclax.

Pharmacokinetics of sertindole in healthy young and elderly male and female subjects

The pharmacokinetic disposition of oral sertindole, a new selective antipsychotic compound, in young and elderly male and female subjects was investigated.

The Pharmacokinetics of Single Oral Doses of Zileuton 200 to 800mg, its Enantiomers, and its Metabolites, in Normal Healthy Volunteers

SummaryThe pharmacokinetics of single oral doses of zileuton 200 to 800mg, its R(+) and S(−) enantiomers, and its Af-dehydroxylated and glucuronide metabolites have been investigated in a randomised study in 16 normal male healthy volunteers.Zileuton was 93.4% bound to plasma proteins. The overall dispositional pharmacokinetics of zileuton racemate appeared to be linear. The mean dosenormalised area under the concentration-time curve from zero to infinity (AUC0-∞) remained constant, while the mean dose-normalised peak plasma concentration (Cmax) decreased with the increase in dose, possibly because of dissolution rate-limited absorption at the higher doses.The R(+) and S(−) enantiomers of zileuton may have similar absorption profiles, although the apparent total plasma clearance of the S(−) enantiomer was 49 to 76% higher than the corresponding values for the R(+) enantiomer. The AUC-∞ of each enantiomer increased proportionately with dose.The pharmacokinetics of the N-dehydroxylated metabolite of zileuton were highly variable, with a more than dose-proportional increase in the mean dosenormalised Cmax and area under the concentration-time curve from zero to 24 hours.The elimination of the glucuronide metabolites of the R(+) and S(−) enantiomers of zileuton was formation rate-limited. The mean percentage of the administered zileuton dose recovered in urine as glucuronide metabolites ranged from 73.1 to 76.5% and showed no dose-related differences. The renal clearances of the glucuronide metabolites of zileuton exceeded the normal glomerular filtration rate, suggesting that these metabolites may be excreted through renal tubular secretion in addition to filtration.

Population pharmacokinetics of telavancin in healthy subjects and patients with infections.

ABSTRACT A population pharmacokinetic model of telavancin, a lipoglycopeptide antibiotic, was developed and used to identify sources of interindividual variability. Data were obtained from healthy subjects (seven phase 1 studies), patients with complicated skin and skin structure infections (cSSSI; two phase 2 and two phase 3 studies), and patients with hospital-acquired pneumonia (HAP; two phase 3 studies). A two-compartment open model with zero-order input best fit the telavancin data from healthy individuals and patients with cSSSI or HAP. Telavancin clearance was highly correlated with renal function and, to a lesser extent, with body weight. Other covariates were related to at least one parameter in cSSSI (gender, bacterial eradication, and surgery) or HAP (age of ≥75 years) but did not markedly affect exposure. These analyses support current dosing recommendations for telavancin based on patient weight and renal function.

Effects of food, antacid, and dosage form on the pharmacokinetics and relative bioavailability of sertindole in healthy volunteers.

The pharmacokinetic disposition and relative bioavailability of sertindole administered as a tablet dosage form under fasting conditions, in the presence of food, in the presence of antacid, and as solution was studied in a four‐way crossover in young healthy male volunteers. Overall, tablet dosing after a meal or Maalox had no effect on t1/2 or AUC values when compared to fasting conditions, but increased the tmax and decreased the Cmax values slightly. The mean relative bioavailabilities of sertindole administered as tablets after fasting, with food, and with Maalox are 99, 104, and 98%, respectively, compared to sertindole solution. Therefore, sertindole can be administered with and without food and without regard to coadministration of antacids.

Effect of Telavancin on the pharmacokinetics of the cytochrome P450 3A probe substrate midazolam: a randomized, double-blind, crossover study in healthy subjects.

Study Objective. To examine the effect of telavancin, a lipoglycopeptide antibiotic with potent gram‐positive activity, on the pharmacokinetics of midazolam, a cytochrome P450 (CYP) 3A probe substrate.